title: Chemokine co-receptor CCR5/CXCR4-dependent modulation of Kv2.1 channel confers acute neuroprotection to HIV-1 glycoprotein gp120 exposure.
abstract: Infection with human immunodeficiency virus-1 (HIV-1) within the brain has long been known to be associated with neurodegeneration and neurocognitive disorder (referred as HAND), a condition characterized in its early stages by declining cognitive function and behavioral disturbances. Mechanistically, the HIV-1 coat glycoprotein 120 (gp120) has been suggested to be a critical factor inducing apoptotic cell death in neurons via the activation of p38 mitogen-activated protein kinase (MAPK), upon chronic exposure to the virus. Here we show that acute exposure of neurons to HIV-1 gp120 elicits a homeostatic response, which provides protection against non-apoptotic cell death, involving the major somatodendritic voltage-gated K⁺ (Kv) channel Kv2.1 as the key mediator. The Kv2.1 channel has recently been shown to provide homeostatic control of neuronal excitability under conditions of seizures, ischemia and neuromodulation/neuroinflammation. Following acute exposure to gp120, cultured rat hippocampal neurons show rapid dephosphorylation of the Kv2.1 protein, which ultimately leads to changes in specific sub-cellular localization and voltage-dependent channel activation properties of Kv2.1. Such modifications in Kv2.1 are dependent on the activation of the chemokine co-receptors CCR5 and CXCR4, and subsequent activation of the protein phosphatase calcineurin. This leads to the overall suppression of neuronal excitability and provides neurons with a homeostatic protective mechanism. Specific blockade of calcineurin and Kv2.1 channel activity led to significant enhancement of non-apoptotic neuronal death upon acute gp120 treatment. These observations shed new light on the intrinsic homeostatic mechanisms of neuronal resilience during the acute stages of neuro-HIV infections.
authors.affiliation: Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Shepherd
authors.forename: Lipin
authors.initials: L
authors.lastname: Loo
authors.forename: Durga P
authors.initials: DP
authors.lastname: Mohapatra
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D019703:Calcineurin / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D005260:Female; D015699:HIV Envelope Protein gp120 / Q000494:pharmacology*; D015497:HIV-1; D006624:Hippocampus / Q000166:cytology*; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D019713:Receptors, CCR5 / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000378:metabolism*; D051669:Shab Potassium Channels / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D015699:HIV Envelope Protein gp120; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D051669:Shab Potassium Channels; C514793:gp120 protein, Human immunodeficiency virus 1; D019703:Calcineurin; D002118:Calcium